The proposed research would be directed at elucidating the role of insulin disposition in insulin homeostasis and possible derangements in diabetes mellitus. To these ends the effect of factors reported to decrease hepatic degradation of insulin, such as starvation and alloxan-diabetes, on the plasma clearance, tissue distribution and degradation of 131I labelled insulin and related peptides would be investigated in the rat. Also, the kinetics, nature, sites and specificity of the degradative and transport processes for 131I insulin and related peptides and the relationships between plasma membrane binding, biological activity and degradation would be investigated in subcellular fraction of rat liver both in vitro and in vivo following intraportal injection of the hormones. The studies would be extended to biopsy specimens of liver of selected non-diabetic and diabetic human subjects. The physiological data would also be utilized to develop comprehensive mathematical models which would predict observed data and account for the physiological processes known or believed to occur. Such models would ultimately be utilized to analyze curves of 131I insulin and related peptide disappearance in plasma of non-diabetic and diabetic subjects to determine the specific causes that produce and influence the magnitudes and rates of change in plasma insulin levels following glucose administration in terms of dynamics reaction rates and turnover.